a. Field of the Invention
The present invention relates generally to hydraulic cements for medical and dental applications, and, more particularly, to an aluminum-and magnesium-free hydraulic cement that produces a nano-dispersed composite of calcium-silicate-hydrate gel mixed with hydroxyapatite, that exhibits good mechanical strength and high biocompatibility and bioactivity.
b. Related Art
Hydraulic cements are commonly utilized in construction and also in medical and dental applications.
One of the most important hydraulic cements is calcium di-silicate and tri-silicate-based cement, which is widely used in construction. There are three main compounds in the cement: dicalcium silicate (C2S), tricalcium silicate (C3S), and calcium aluminate (C3A). Highly crystalline calcium hydroxide (Ca(OH)2) (referred to later as CH) and amorphous calcium-silicate-hydrate (C—S—H) are the principal phases that form in the hydration process of C2S and C3S. The hydrated cement paste consists of approximately 70% C—S—H and 20% CH, with additional phases including about 7% sulfoaluminate, and about 3% of secondary phases. The calcium hydroxide component, which is formed as a result of the setting reaction, negatively effects the quality of the set cement, since CH is soluble in water and has low strength.
Certain Portland cement—based materials (referred to as mineral trioxide aggregate, or MTA) have been used for medical and dental applications, such as endodontic dental treatment and the retention of cores [Vargas et al., “A Comparison of the In vitro Retentive Strength of Glass-Ionomer Cement, Zinc-Phosphate Cement, and Mineral Trioxide Aggregate for the Retention of Prefabricated Posts in Bovine Incisors” J. Endodont. 30(11) 2004, 775-777]. MTA, like Portland cement, consists primarily of tricalcium silicate, tricalcium oxide, and tricalcium aluminates. [Torabinejad et al. “Physical and chemical properties of a new root-end filling material”. J Endodont 21(1995) 349-253]. The hydration product of calcium aluminates is a mixture of calcium-aluminate compounds and calcium-sulfate-aluminate compounds [Concrete, J. F. Young, pp76-98, Prentice-Hall, Inc, Englewood Cliffs, 1981].
MTA, has been used in many surgical and non-surgical applications, and possesses the biocompatibility and sealing abilities requisite for a perforation material [Lee, et al, “Sealing ability of a mineral trioxide aggregate for repair of lateral root perforations” J Endod 1993; 19:541-4.]. It can be used both as a non-absorbable barrier and restorative material for repairing root perforations. Because it is a hydrophilic cement and requires moisture to set, MTA has been the barrier of choice when there is potential for moisture contamination, or when there are restrictions in technical access and visibility during the restorative process. MTA also has good compressive strength after setting.
In one example, Torabinejad et al (U.S. Pat. Nos. 5,415,547, and 5,769,638) disclosed an improved method for filling and sealing tooth cavities which involved the use of an MTA cement composition, including the ability to set in an aqueous environment. The cement composition comprises Portland cement, or variations on Portland cement, which exhibits physical attributes sufficient to form an effective seal against re-entrance of infectious organisms. However, the MTA composition derived from Portland cement is gray in color, which is unsuitable for many dental applications. Moreover, among other problems, MTA contains significant amounts of aluminum and consequently presents certain biocompatibility and toxicity concerns, as will be discussed below.
Primus (U.S. Pat Appl. 20030159618) disclosed a process for making a white, substantially non-iron containing dental material formed from Portland cement. The material, also referred to as White MTA or WMTA, may be used as a dental cement, dental restorative or the like. However, this process only decreases the iron content and does not improve the biological properties of the material, since it still contains aluminum.
A number of investigators have reported improvement of mechanical strength of Portland cement by adding silica fume (SiO2, referred later as S) in order to decrease Ca(OH)2 content in the hydrated cement [Mitchell, Et Al, “Interaction Of Silica Fume With Calcium Hydroxide Solutions And Hydrated Cement Pastes”, Cement And Concrete Research (1998), 28(11), 1571-1584 And Persson “Seven-Year Study On The Effect Of Silica Fume In Concrete” Advanced Cement Based Materials (1998), 7(3/4), 139-155]. The mechanism depends on the silica fume reacting with the calcium hydroxide CH to produce an amorphous C—S—H gel having a high density and low Ca/Si ratio. This demonstrates that removal of CH can make for substantial improvement of the set cement.
The foregoing effect was also recognized in Japanese patent no. JP 11-292600 “Production of slightly calcium leaching cement composition.” (Oct. 26, 1999). The patent disclosed a “slightly calcium leaching Portland cement composition” with a phosphate or fluorides added to the cement material (e.g. Portland cement). The resulting product is a cement hydrate with reduced production in calcium hydroxide and an increase of calcium phosphate compounds, e.g. hydroxyapatite. The material is designated for treatment of hazardous wastes, such as nuclear waste, to prevent leaching, and also for construction materials and structural materials, which would include relatively high levels of impurities and consequently exhibit toxicity unsuitable for medical/dental use. Moreover, when Portland cement is combined with “phosphoric acid compounds” or fluorides, aluminum phosphate or aluminum fluoride result. Aluminum compounds are therefore present in this material as well, similar to the situation with MTA.
The presence of aluminum is a major disadvantage of the materials derived from Portland cement (such as MTA or WMTA) when used for biomedical and dental applications. Aluminum ions will be released into human biological system during hydration and setting reaction of such cement. Moreover, in the case of permanent and long term applications, such as dental filling, bone implants, and use in orthopedic surgery, the calcium sulfate aluminates in the cements will continually release aluminum ions into the human biological system [Fridland, et al., “MTA Solubility: A Long Term Study”, JOE—Volume 31, Number 5, May 2005, and JOURNAL OF ENDODONTICS, VOL. 29, NO. 12, DECEMBER 2003].
Research indicates that aluminum ions are toxic to the human biological system. For example, aluminum inhibits mineralization of bone, and is toxic to osteoblasts. Diseases that have been associated with aluminum include dialysis dementia, renal osteodystrophy and Alzheimer's disease. Aluminum also has adverse effect on red blood cells, parathyroid glands and chromosomes. Accumulation of aluminium in the body tends to occur when the gastrointestinal barrier is circumvented, as is the case with implants or dental treatments. See for example, Monteagudo, et al., “Recent developments in aluminum toxicology”, Medical toxicology and adverse drug experience (1989 January-February), 4(1), 1-16. Ref: 158; Rodriguez, et al., “Aluminum administration in the rat separately affects the osteoblast and bone mineralization”, J Bone Miner Res 1990 January;5(1):59-67; SAVARINO. et al., “In vitro investigation of aluminum and Fluoride release from compomers, conventional and resin-modi. Ed glass-ionomer cements: A standardized approach,” J. Biomater. Sci. Polymer Edn, Vol. 11, No. 3, pp. 289-300 (2000). One commonly observed result of the awareness of aluminum toxicity to human bodies is the gradual elimination of aluminum cooking utensils from general (and in particular household) use, and their replacement by stainless steel utensils; this process continues despite the fact that aluminum utensils provide excellent heat transfer characteristics due to high thermal conductivity (up to 300 W/mK), as opposed to the relatively low thermal conductivity (and significantly higher cost) of stainless steel.
All of the prior cement compositions discussed above are based on (or derived from) Portland cement, and as such rely on aluminum compounds to achieve early strength when setting. If the aluminum were to be removed from such compositions, the strength increase would be much slower, rendering the cement useless for its intended applications. As will be described below, the hydraulic cement of the present invention does not use aluminum, and instead, employs inventive materials science (e.g., inclusion of kinetics-accelerating phosphate compounds) and processing methods (e.g., controlled particle size) to achieve early setting strength without aluminum compounds.
There are instances reported in the literature where phosphates have been combined with calcium-silicate Portland-type cements. For example Ma et al [“Effect of phosphate additions on the hydration of Portland cement” Advances in Cement Research (1994), 6(21), 1-12] discussed the effect of phosphate additions on the hydration process of Portland cement. The phosphate-modified cements, which were not designed for biomedical applications, produced more hydration heat and exhibited faster hydration rates than the reference ordinary Portland cement. The reaction products were amorphous, but hydrothermal treatment at 160° C. of ordinary Portland cement (OPC) modified by CaHPO4 allowed transformation of a poorly crystalline phosphate phase into hydroxyapatite, resulting in improved flexural strengths. A number of disadvantages limit the applications of the process, such as the need for hydrothermal treatment for formation of the hydroxyapatite, and the need for high pressure (28 MPa) pressing in order to achieve an adequately high strength. Also, the process described by Ma et al can not be used for forming a uniform composite structure, and the mechanical strength was not significantly improved by comparison with Ordinary Portland cement (OPC). Moreover, the cements still relied on aluminum compounds to gain early strength. Recently, U.S. Pat. No. 7,083,672 (Wagh et al) disclosed phosphosilicate ceramics comprising 65-85 weight percent of a powder and about 15-35 weight percent of a liquid, which are combined to form a paste for various uses, for example, as a bone cement for dental and orthopedic purposes. The powder component comprises a “sparsely soluble oxide” powder, such as magnesium oxide powder, monovalent alkali metal phosphate powder and a sparsely soluble silicate powder (e.g. CaSiO3). The liquid component comprises a pH modifying acid (e.g. Ca(H2PO4)2H2O), such that pH is in the range of 3-7 (preferably nearly 3) during setting of the cement. Hydroxyapatite (HAP) powder may be introduced into the composition by admixing an HAP powder into the other powder; there is no provision for reactive, in-situ formation of HAP, which limits the possibilities of composite formation, and also provides less than satisfactory mechanical properties and bioactivity/biocompatibility in the set material.
Chemically bonded ceramics (CBC) in the system CaO—SiO2—P2O5—H2O were investigated by Hu et al [“Investigation of hydration phases in the system CaO—SiO2—P2O5—H2O” J. Mater. Res. 1988, 3(4) 772-78] and Sterinke et al [Development of chemically bonded ceramics in the system CaO—SiO2—P2O5—H2O” Cement and Concrete Res. 1991 (21)66-72]. The powders of CBC were synthesized by sol-gel process and then fired at a temperature of 700-1000 C for 2 hours. The components of the powders before hydration are calcium hydroxyapatite (major), di-calcium silicate, γ-2CaO—SiO2, amorphous calcium silicate, and amorphous calcium phosphate [Hu, et al, “Studies of strength mechanism in newly developed chemically bonded ceramics in the system CaO—SiO2—P2O5—H2O” Cement and Concrete Res. 1988 (18)103-108]. However, the mechanical properties were not improved when the samples were hydrated at room temperature. In order to increase the mechanical strength of CBC, the samples were made with high pressure formation (345 MPa) and were subsequently hydrated at high temperatures.
Calcium phosphate cement (CPC) was first reported in a binary system containing tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrate (DCPA) [L. C. Chow et al. J. Dent Res., 63, 200, 1984]. The advantages of CPC include self-setting (similar to OPC), plus an apatitic phase in the set cement (e.g. HAP, or other similar phases of varying chemistry and crystallinity). Consequently, CPC is a bio-active material that interract with body fluids through a dissolution-reprecipitation process. This has led to applications such as bone replacement and reconstruction, and also drug delivery [M Dairra, et al. Biomaterials, 19 1523-1527, 1998; M. Otsuka, et al. J. of Controlled Release 43(1997)115-122, 1997, Y. Tabata, PSTT, Vol. 3, No. 3, 80-89, 2000; M. Otsuka, et al. J. of Pharm. Sci. Vol. 83, No. 5, 1994].
Calcium phosphate cement (CPC) is typically formulated as a mixture of solid and liquid components in pertinent proportions, which react to form the apatite. The physicochemical reactions that occur upon mixing of the solid and liquid components are complex, but dissolution and precipitation are the primary mechanisms responsible for the final apatite formation [C. Hamanish et al J. Biomed. Mat. Res., Vol. 32, 383-389, 1996; E. Ferandez et al J. Mater. Sci. Med. 10, 1999]. The reaction pathway in most CPC systems does not lead to stoichiometric HAP, but rather to calcium-deficient Ca10-x(HPO4)x(PO4)6-x(OH)2-x, similar to that found in bone. The process parameters, such as Ca/P ratio, powder/liquid ratio, seeds concentration type, and nature of reagents, control the final properties, such as phase content, porosity, strength, setting time, phase transformation kinetics, and microstructure of the CPC-derived hydroxyapatite (CPC-HAP). Synthetic CPC may also incorporate carbon-containing phases, similar to bone minerals.
Bermudez et al [J. Mat. Sci. Med. 4, 503-508, 1993; ibid 5, 67-71, 1994] correlated the compressive strength of CPC to the starting Ca/P ratio in systems of monocalcium phosphate monohydrate (MCPM) and calcium oxide. The major drawback of CPC technology is low mechanical strength (generally below 20 MPa compressive), which severely limits its suitability for medical/dental materials and devices. Intensive research continues on increasing strength of CPC, for example sophisticated processing methods involving reduction or elimination of flaws (such as voids or cracks) from set cement have been reported [T Troczynski, “Bioceramics-A Concrete Solution”, Nature Materials, [3] 13-14, January 2004]. As CPC behaves as a typical brittle, flaw-sensitive ceramic, reduction of flaws translates to increased strength. However, substantial elimination of flaws in CPC setting in contact with living tissue such as bone or dentine may be impractical or impossible. In some situations it is also not desirable, as hard tissue such as bone may integrate easier with porous CPC as compared to dense CPC. There is constantly a continuing need to be able to increase strength of biological cements without substantial modification of their porosity or flaws density.
A combination of the oxides of calcium, phosphorous and silicon (with the major component being silica, in an amount of about 45 wt %) results in a bioactive glass material, providing excellent in-vivo performance and stimulation of cell growth, sometimes even better than hydroxyapatite or other calcium phosphates [e.g. Oonishi et al, “Particulate Bioglass compared with hydroxyapatite as a bone graft substitute”, J. Clin. Orthop. Rel. Res. 334, 316-25, 1997; also U.S. Pat. No. 5,811,302 by Ducheyne et al, Sep. 22, 1988]. This is an indication that the biomaterials synthesized through combination of the three oxides of calcium, phosphorous and silicon may become even more bioactive than calcium phosphates that lack silica. This observation has been explored by partial replacement of Ca by Si in the solid solution through high-temperature treatment and sintering [e.g. compare US Pat. Appl. 20030003160, Jan. 2, 2003, S. M. Pugh et al, “Synthetic biomaterial compound of calcium phosphate phases particularly adapted for supporting bone cell activity”]. Unfortunately, although chemically advantageous, bio-glass must be processed at very high temperatures (generally in excess of 1000 C), and is a rather dense, weak and brittle material. Another disadvantage of bio-glass is that it does not easily dissolve in biological environments (due to dense SiO2 film coverage), which is desirable in some applications, e.g. for stimulation of bone growth.
The literature has recently reported attempts to address these issues, by combining the three oxides of calcium, phosphorous and silicon into porous crystalline composite material, which would possess a high bioactivity similar to the bio-glass, but which would be stronger (even though porous) and easier to resorb in-vivo [A. R. El-Ghannam, “Advanced bioceramics composite for bone tissue engineering: design principles and structure-bioactivity relationship”, J. Biomed. Mater. Res. 69A, 490-501, 2004]. The precursors to the three oxides (plus sodium oxide) were heat treated at high temperatures (130-800 C) to result in a porous composite of crystalline silica (quartz or crystobalite), and variety of calcium-phosphates or calcium-sodium-phosphates. Excellent bioactivity of these composites was demonstrated. Unfortunately the need for the high temperature treatment makes this composite material difficult to apply as biomaterial, as all the processing and shaping operations must take place outside of the application site.
The advantages of the simultaneous presence of Ca, P, and Si elements in bioceramic materials has been also recognized through sinter-processing (high temperature heat treatment) of silicon substituted hydroxyapatite and other calcium phosphates [Alexis M Pietak, Joel W. Reid, Michael Sayer, “Electron spin resonance in silicon substituted apatite and tricalcium phosphate”, Biomaterials, June 2005, p3-14; Joel W. Reid, Loughlin Tuck, Michael Sayer, Karen Fargo and Jason A. Hendry, “Synthesis and characterization of single-phase silicon-substituted α-tricalcium phosphate,” Biomaterials, Volume 27, Issue 15, May 2006, Pages 2916-2925]. The need for high-temperature processing of the biomaterials is a drawback of this approach as well, similar to the bioglass described above.
The bioglass, calcium phosphates, and all cements in the CPC family of cement, are unstable in biological environments, and eventually dissolve, frequently providing room and a chemical environment encouraging growth of new tissue, such as bone tissue. However, in many applications, such as endodontics or orthopedic applications where the cement must have sufficient strength at all times, resorption is not desirable. The present invention is directed to non-resorbable biological cements that are based on calcium silicates.
Accordingly, there exists a need for a hydraulic cement for use in medical and dental applications that is free from aluminum and other elements/compounds which present potential toxicity problems in a biological system. Still further, there exists a need for such a hydraulic cement that is biocompatible with the surrounding tissue and system in additional respects, and that exhibits a high degree of bioactivity. Furthermore, there exists a need for such a hydraulic cement which can set and gain sufficient strength at room or near-room temperatures (such as body temperature). Still further, there exists a need for such a hydraulic cement which, when set, will exhibit substantially no resorption during lifetime of the implant Still further, there exists a need for such a hydraulic cement that develops sufficiently high strength, stability and resistance to fracture/brakage to be suitable for use as a bone substitute, in dental work, in orthopedic surgery, and in other medical and dental applications. Still further, there exists a need for such a hydraulic cement that can be placed and set under temperatures, pH levels and other conditions that are compatible with the human biological system.